Using isolated rabbit hearts in experiments outlined in detail herein, we have found that regulation of coronary flow to changes in perfusion pressure involves two components; (a) a passive one in the form of a fixed resistance to flow, or vascular tone, which is dependent on a vasoconstrictor present in plasma, (b) an active component which can operate in the absence of plasma. Both are required for effective regulation of flow; the magnitude of the active component is not sufficient in the absence of plasma. The active responses to changes in myocardial activity and hypoxia also occur in the absence of plasma. However, at the higher physiological perfusion pressures, these responses are ineffective in the absence of the fixed resistance to flow provided by the plasma vasoconstrictor. In isolated hearts in which endogenous prostaglandin synthesis was inhibited with indomethacin, the active response to changes in perfusion pressure, myocardial activity, and perfusate pO2 still occurred. Thus, these responses do not require endogenous prostaglandins. However, indomethacin did effect the rate at which the response to changes in perfusate pO2 occurred. If endogenous prostaglandins act on the rate of response rather than the magnitude of response, many of the conflicting reports concerning the role of prostaglandins in regulation of coronary flow could be explained. Our comparison of the responses to changes in perfusion pressure, myocardial activity and perfusate pO2 has uncovered differences in the responses. We plan to explore these differences and to complete our studies concerning the role of prostaglandins in controlling the rates of responses with an aim at elucidating the mechanisms involved in local regulation of coronary flow.